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. 1992 May;33(5):701–706. doi: 10.1136/gut.33.5.701

Effective peritoneal therapy of acute pancreatitis in the rat with glutaryl-trialanin-ethylamide: a novel inhibitor of pancreatic elastase.

P Fric 1, J Slabý 1, E Kasafírek 1, P Kocna 1, J Marek 1
PMCID: PMC1379306  PMID: 1377154

Abstract

The six hour peritoneal lavage with glutaryl-trialanin-ethylamide, a low molecular competitive inhibitor of pancreatic elastase (IC50-8 mumol/l), effectively suppresses the evolution of taurocholate induced acute pancreatitis in the rat. The lavage alone is followed by a marked decrease of fat necrosis and amylase and lipase activity in serum. The area of pancreatic haemorrhage was significantly reduced only after the lavage solution was supplemented with Glt-Ala3-NHEt. The effect was not enhanced by a bolus injection of the inhibitor before starting the lavage. The combination of Glt-Ala3-NHEt with aprotinin or nafamstate mesilate produced only marginal greater benefit. The effect of Glt-Ala3-NHEt on pancreatic haemorrhage is time and dose related even with delayed onset of the lavage. Animals treated with peritoneal lavage without Get-Ala3-NHEt lived longer than controls (p less than 0.05), but by 60 hours the survival rate of both groups was almost the same (76 v 74%). All animals lavaged with Glt-Ala3-NHEt survived 120 hours and the difference in the survival rate between this and both remaining groups was significant (100% v 76% v 74% - p less than 0.05). The results were considered favourable and preliminary clinical trials of Glt-Ala3-NHEt in subjects with acute pancreatitis justified.

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Selected References

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  1. Abrahamian V., Huk I., Kaminski M. V., Jr A new method for long-term intravenous alimentation in unrestrained rats. JPEN J Parenter Enteral Nutr. 1984 Sep-Oct;8(5):581–584. doi: 10.1177/0148607184008005581. [DOI] [PubMed] [Google Scholar]
  2. Balldin G., Borgström A., Genell S., Ohlsson K. The effect of peritoneal lavage and aprotinin in the treatment of severe acute pancreatitis. Res Exp Med (Berl) 1983;183(3):203–213. doi: 10.1007/BF01855643. [DOI] [PubMed] [Google Scholar]
  3. Bassi C., Briani G., Vesentini S., Orcalli F., Falconi M., Vantini I., Cavallini G., Maffezzoli G., Pederzoli P. Continuous peritoneal dialysis in acute experimental pancreatitis in dogs. Effect of aprotinin in the dialysate medium. Int J Pancreatol. 1989 Jul;5(1):69–75. doi: 10.1007/BF02925699. [DOI] [PubMed] [Google Scholar]
  4. Buggy B. P., Nostrant T. T. Lethal pancreatitis. Am J Gastroenterol. 1983 Dec;78(12):810–814. [PubMed] [Google Scholar]
  5. Fric P., Kasafírek E., Slabý J., Malis F. Determination of pancreatic elastase with new chromogenic substrates-p-nitroanilides of N-acyltripeptides. Acta Univ Carol Med Monogr. 1977;(79 Pt 3):183–191. [PubMed] [Google Scholar]
  6. Fric P., Kasafírek E., Slabý J., Marek J. Effect of new oligopeptide inhibitors of elastase on acute experimental pancreatitis in the rat. Hepatogastroenterology. 1985 Aug;32(4):206–209. [PubMed] [Google Scholar]
  7. Fric P., Kasafírek E., Slabý J. New low-molecular inhibitors of pancreatic elastase with possible in vivo application: alkylamides of N-acylated tripeptides. Experientia. 1983 Apr 15;39(4):374–375. doi: 10.1007/BF01963130. [DOI] [PubMed] [Google Scholar]
  8. Geokas M. C., Murphy R., McKenna R. D. The role of elastase in acute pancreatitis. I. Intrapancreatic elastolytic activity in bile-induced acute pancreatitis in dogs. Arch Pathol. 1968 Aug;86(2):117–126. [PubMed] [Google Scholar]
  9. Geokas M. C. The role of elastase in acute pancreatitis. II. Intrapancreatic elastolytic activity in trypsin-induced acute pancreatitis in dogs. Arch Pathol. 1968 Aug;86(2):127–134. [PubMed] [Google Scholar]
  10. Imrie C. W. Peritoneal lavage in severe acute pancreatitis. Br J Surg. 1985 Sep;72(9):677–677. doi: 10.1002/bjs.1800720902. [DOI] [PubMed] [Google Scholar]
  11. Kasafírek E., Fric P., Malis F. The significance of the N-acyl residue of L-alanyl-L-alanyl-L-alanine p-nitroanilide for cleavage by pancreatic elastase. FEBS Lett. 1974 Apr 1;40(2):353–356. doi: 10.1016/0014-5793(74)80262-0. [DOI] [PubMed] [Google Scholar]
  12. Kasafírek E., Fric P., Slabý J. Anionic inhibitors of pancreatic and leukocyte elastase. Alkylamides of 3-carboxypropionyl- and 4-carboxybutyrylalanine peptides. Biol Chem Hoppe Seyler. 1985 Apr;366(4):333–343. doi: 10.1515/bchm3.1985.366.1.333. [DOI] [PubMed] [Google Scholar]
  13. Kasafírek E., Fric P., Slabý J., Malis F. p-Nitroanilides of 3-carboxypropionyl-peptides. Their cleavage by elastase, trypsin, and chymotrypsin. Eur J Biochem. 1976 Oct 1;69(1):1–13. doi: 10.1111/j.1432-1033.1976.tb10852.x. [DOI] [PubMed] [Google Scholar]
  14. Lankisch P. G., Koop H., Winckler K., Schmidt H. Continuous peritoneal dialysis as treatment of acute experimental pancreatitis in the rat. I. Effect on length and rate of survival. Dig Dis Sci. 1979 Feb;24(2):111–116. doi: 10.1007/BF01324737. [DOI] [PubMed] [Google Scholar]
  15. Lankisch P. G., Koop H., Winckler K., Schmidt H. Continuous peritoneal dialysis as treatment of acute experimental pancreatitis in the rat. II. Analysis of its beneficial effect. Dig Dis Sci. 1979 Feb;24(2):117–122. doi: 10.1007/BF01324738. [DOI] [PubMed] [Google Scholar]
  16. Lankisch P. G., Pohl U., Göke B., Otto J., Wereszczynska-Siemiatkowska U., Gröne H. J., Rahlf G. Effect of FOY-305 (camostate) on severe acute pancreatitis in two experimental animal models. Gastroenterology. 1989 Jan;96(1):193–199. doi: 10.1016/0016-5085(89)90780-4. [DOI] [PubMed] [Google Scholar]
  17. Lankisch P. G., Winckler K., Bokermann M., Schmidt H., Creutzfeldt W. The influence of glucagon on acute experimental pancreatitis in the rat. Scand J Gastroenterol. 1974 Nov;9(8):725–729. [PubMed] [Google Scholar]
  18. Larvin M., Mayer A. D., McMahon M. J., Müller-Esterl W., Fritz H. Intra-peritoneal aprotinin therapy for acute pancreatitis. Preliminary pharmacodynamic studies. Biol Chem Hoppe Seyler. 1988 May;369 (Suppl):149–152. [PubMed] [Google Scholar]
  19. Lasson A., Balldin G., Genell S., Ohlsson K. Peritoneal lavage in severe acute pancreatitis. Acta Chir Scand. 1984;150(6):479–484. [PubMed] [Google Scholar]
  20. Leonhardt U., Seidensticker F., Fussek M., Stöckmann F., Creutzfeldt W. Camostate (FOY-305) improves the therapeutic effect of peritoneal lavage on taurocholate induced pancreatitis. Gut. 1990 Aug;31(8):934–937. doi: 10.1136/gut.31.8.934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mayer A. D., McMahon M. J., Corfield A. P., Cooper M. J., Williamson R. C., Dickson A. P., Shearer M. G., Imrie C. W. Controlled clinical trial of peritoneal lavage for the treatment of severe acute pancreatitis. N Engl J Med. 1985 Feb 14;312(7):399–404. doi: 10.1056/NEJM198502143120703. [DOI] [PubMed] [Google Scholar]
  22. Niederau C., Crass R. A., Silver G., Ferrell L. D., Grendell J. H. Therapeutic regimens in acute experimental hemorrhagic pancreatitis. Effects of hydration, oxygenation, peritoneal lavage, and a potent protease inhibitor. Gastroenterology. 1988 Dec;95(6):1648–1657. doi: 10.1016/s0016-5085(88)80091-x. [DOI] [PubMed] [Google Scholar]
  23. Ohlsson K., Tegner H. Experimental pancreatitis in the dog. Demonstration of trypsin in ascitic fluid, lymph and plasma. Scand J Gastroenterol. 1973;8(2):129–133. [PubMed] [Google Scholar]
  24. Ranson J. H. Conservative surgical treatment of acute pancreatitis. World J Surg. 1981 May;5(3):351–359. doi: 10.1007/BF01657994. [DOI] [PubMed] [Google Scholar]
  25. Satake K., Koh I., Nishiwaki H., Umeyama K. Toxic products in hemorrhagic ascitic fluid generated during experimental acute hemorrhagic pancreatitis in dogs and a treatment which reduces their effect. Digestion. 1985;32(2):99–105. doi: 10.1159/000199225. [DOI] [PubMed] [Google Scholar]
  26. Steinberg W. M., Schlesselman S. E. Treatment of acute pancreatitis. Comparison of animal and human studies. Gastroenterology. 1987 Dec;93(6):1420–1427. doi: 10.1016/0016-5085(87)90275-7. [DOI] [PubMed] [Google Scholar]
  27. Van Hee R., Van Elst F., Van Rooy F., Van Haasen R., Hubens A. Peritoneal lavage in acute pancreatitis. An experimental and clinical study. Acta Chir Belg. 1981 Nov-Dec;80(6):397–402. [PubMed] [Google Scholar]
  28. Wilson C., Imrie C. W. Effective intraperitoneal antiprotease therapy for taurocholate-induced pancreatitis in rats. Br J Surg. 1990 Nov;77(11):1252–1255. doi: 10.1002/bjs.1800771118. [DOI] [PubMed] [Google Scholar]

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